Melanoma therapy

ABSTRACT

Methods for treating treatment-naive as well as treatment-experienced patients having melanoma to increase the progression-free survival time involving administering a therapeutically effective amount of pegylated interferon-alpha, e.g., preferably pegylated interferon alpha-2b, as adjuvant therapy to definitive surgery are disclosed.

[0001] This application claims the benefit of U.S. provisional patentapplication Ser. No. 60/128,308 filed Apr. 8, 1999.

[0002] Throughout this disclosure, various publications, patents andpatent applications are referenced. The disclosures of thesepublications, patents and patent applications are herein incorporated byreference.

BACKGROUND OF THE INVENTION

[0003] This invention relates to an improved therapy for treatingpatients having melanoma after definitive surgical removal of thelesions by administering a therapeutically effective dose of pegylatedinterferon-alpha for a time sufficient to increase progression-freesurvival time.

[0004] Melanoma incidence is increasing at a rate that exceeds all thatfor other solid tumors. Patients with primary melanoma of greater than 4mm or metastatic melanoma involving regional lymph nodes possess a 50 to90% mortality risk following surgical excision of the primary melanomas.

[0005] Recently, the Eastern Cooperative Oncology Group (“ECOG”)published results of the use of interferon alpha-2b in patients withstage III cutaneous melanoma as adjuvant therapy following surgery fordeep primary (T4) or regionally metastatic (N1) melanoma (Kirkwood, J.M., et al. J. Clin. Oncol., Vol 14: (1996) pages 4-17.) The interferonalpha-2b therapy used by ECOG involved an induction phase of 20 millionIU of interferon alpha-2b per square meter of body surface area (m²)administered intravenously (“IV”) daily for five days every week forfour weeks followed by maintenance interferon alpha therapy of 10million IU/m² administered subcutaneously (“SC”) three times a week(“TIW”) for 48 weeks. A significant improvement in median disease-freesurvival and overall survival were observed versus control (observation)despite dosage reductions or delays for toxicity in 50% of the patientsduring the IV induction therapy phase and in 48% of the patients in theSC maintenance phase. Hematologic, neurologic and constitutionaltoxicities occurred among these patients requiring dose reduction orwithdrawal from the interferon alpha therapy. Subject compliance withthe dosage and dosage regimen during both phases is considered to beimportant to achieve maximum clinical benefit. Accordingly, there is aneed for improved therapy for treating patients having melanoma withhigher patient compliance.

SUMMARY OF THE INVENTION

[0006] The present invention provides a method of treating a patienthaving melanoma which has been surgically removed, which comprisesadministering to such a patient a therapeutically effective dose ofpegylated interferon alpha for a time period sufficient to increase theprogression-free survival time.

[0007] The present invention also provides a method of treating apatient having cutaneous melanoma which has been surgically removed,which comprises administering to said patient an effective amount ofpegylated interferon-alpha once a week for a time period sufficient toincrease progression-free survival time.

[0008] The present invention further provides a method of treating apatient having cutaneous melanoma which has been surgically removedwhich comprises administering to such a patient about 3.0 micrograms/kgto about 9.0 micrograms/kg of pegylated interferon alpha-2b once a weekfor a time period sufficient to increase progression-free survival time.In preferred embodiments, 6.0 micrograms per kilogram is dosed weekly toa patient for eight weeks, and 3.0 micrograms per kilogram or lessweekly is dosed to the patient for a period of five years minus theeight weeks of initial dosage. If less than 3.0 micrograms per kilogramare dosed to the patient, preferably the dose reduction steps are3.0-2.0-1.0 micrograms per kilogram.

[0009] The present invention further provides a method comprising thestep of marketing a therapeutically effective dose of interferon alphafor administration to a patient with melanoma within about 60 days ofsurgery in a protocol extending for a time period of at least about 100weeks.

DETAILED DESCRIPTION OF THE INVENTION

[0010] The present invention provides an improved method of treatingpatients with melanoma especially those in State IIB (lesions >4 mm, butwithout positive nodes)and Stage III (lesions >4 mm and node-positive)primary cutaneous melanoma, preferably after surgery for their State IIBor Stage III melanoma. The improved method provides a safer and moreefficacious and tolerable adjuvant therapy treatment for melanoma by useof weekly injections of pegylated interferon. The melanoma patientstreatable in accordance with the improved method of the presentinvention include those newly diagnosed with this disease who were freeof disease 56 days post surgery but at high risk for systemic recurrenceof the disease. The term “high risk patients” as used herein means thosemelanoma patients with lesions of Breslow thickness >4 mm as well asthose patients with lesions of any Breslow thickness with primary orrecurrent nodal involvement. Melanoma patients intolerant or resistantto interferon alpha therapy are also included. Treatment with pegylatedinterferon alpha in accordance with the present invention will continuefor a minimum of about two years (about 100-104 weeks) and up to fiveyears, unless there is clinical evidence of disease progression,unacceptable toxicity or the patient requests that the therapy bediscontinued.

[0011] When the pegylated interferon-alpha administered is a pegylatedinterferon alpha-2b, the therapeutically effective amount of pegylatedinterferon alpha-2b administered is in the range of about 3.0 to about9.0 micrograms per kilogram of pegylated interferon alpha-2badministered once a week (QW), preferably in the range of about 4.5 toabout 6.5 micrograms per kilogram of pegylated interferon alpha-2b QW,more preferably in the range of about 5.5 to about 6.5 micrograms perkilogram of pegylated interferon alpha-2b QW, and most preferably in therange of about 6.0 micrograms per kilogram of pegylated interferonalpha-2b administered QW.

[0012] In preferred embodiments, 6.0 micrograms per kilogram is dosedweekly to a patient for eight weeks, and 3.0 micrograms per kilogram orless weekly is dosed to the patient for a period of five years minus theeight weeks of initial dosage. If less than 3.0 micrograms per kilogramare dosed to the patient, preferably the dose reduction steps are3.0-2.0-1.0 micrograms per kilogram.

[0013] When the pegylated interferon-alpha administered is a pegylatedinterferon alpha-2a, the therapeutically effective amount of pegylatedinterferon alpha-2a administered is in the range of about 50 microgramsto about 500 micrograms once a week (“QW”), preferably about 200micrograms to about 250 micrograms QW.

[0014] The term “pegylated interferon alpha” as used herein meanspolyethylene glycol modified conjugates of interferon alpha, preferablyinterferon alpha-2a and -2b. The preferredpolyethylene-glycol-interferon alpha-2b conjugate is PEG₁₂₀₀₀-interferonalpha 2b. The phrases “12,000 molecular weight polyethylene glycolconjugated interferon alpha” and “PEG₁₂₀₀₀-IFN alpha” as used hereinmean conjugates such as are prepared according to the methods ofInternational Application No. WO 95/13090 and containing urethanelinkages between the interferon alpha-2a or -2b amino groups andpolyethylene glycol having an average molecular weight of 12000.

[0015] The preferred PEG₁₂₀₀₀-interferon alpha-2b is prepared byattaching a PEG polymer to the epsilon amino group of a lysine residuein the IFN alpha-2b molecule. A single PEG₁₂₀₀₀ molecule is conjugatedto free amino groups on an IFN alpha-2b molecule via a urethane linkage.This conjugate is characterized by the molecular weight of PEG₁₂₀₀₀attached. The PEG₁₂₀₀₀-IFN alpha-2b conjugate is formulated as alyophilized powder for injection. The objective of conjugation of IFNalpha with PEG is to improve the delivery of the protein bysignificantly prolonging its plasma half-life, and thereby provideprotracted activity of IFN alpha.

[0016] The term “interferon-alpha” as used herein means the family ofhighly homologous species-specific proteins that inhibit viralreplication and cellular proliferation and modulate immune response.Typical suitable interferon-alphas include, but are not limited to,recombinant interferon alpha-2b such as Intron-A interferon availablefrom Schering Corporation, Kenilworth, N.J., recombinant interferonalpha-2a such as Roferon interferon available from Hoffmann-La Roche,Nutley, N.J., recombinant interferon alpha-2C such as Berofor alpha 2interferon available from Boehringer Ingelheim Pharmaceutical, Inc.,Ridgefield, Conn., interferon alpha-n1, a purified blend of naturalalpha interferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon such asthose described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especiallyExamples 7, 8 or 9 thereof and the specific product available fromAmgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixture ofnatural alpha interferons made by Interferon Sciences and available fromthe Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.The use of interferon alpha-2a or alpha-2b is preferred. Sinceinterferon alpha-2b, among all interferons, has the broadest approvalthroughout the world for treating chronic hepatitis C infection, it ismost preferred. The manufacture of interferon alpha-2b is described inU.S. Pat. No. 4,530,901.

[0017] Other interferon alpha conjugates can be prepared by coupling aninterferon alpha to a water-soluble polymer. A non-limiting list of suchpolymers include other polyalkylene oxide homopolymers such aspolypropylene glycols, polyoxyethylenated polyols, copolymers thereofand block copolymers thereof. As an alternative to polyalkyleneoxide-based polymers, effectively non-antigenic materials such asdextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols,carbohydrate-based polymers and the like can be used. Such interferonalpha-polymer conjugates are described in U.S. Pat. No. 4,766,106, U.S.Pat. No. 4,917,888, European Patent Application No. 0 236 987, EuropeanPatent Application Nos. 0 510 356 , 0 593 868 and 0 809 996 (pegylatedinterferon alpha-2a) and International Publication No. WO 95/13090.

[0018] Pharmaceutical composition of pegylated interferon alpha-suitablefor parenteral administration may be formulated with a suitable buffer,e.g., Tris-HCl, acetate or phosphate such as dibasic sodiumphosphate/monobasic sodium phosphate buffer, and pharmaceuticallyacceptable excipients (e.g., sucrose), carriers (e.g. human serumalbumin), toxicity agents (e.g. NaCl), preservatives (e.g. thimerosol,cresol or benylalcohol), and surfactants(e.g. tween or polysorabates) insterile water for injection. The pegylated interferon alpha-may bestored as lyophilized powders under a refrigeration at 2°-8° C. Thereconstituted aqueous solutions are stable when stored between 2° and 8°C. and used within 24 hours of reconstitution. See for example U.S. Pat.Nos. 4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueoussolutions may also be stored in prefilled, multi-dose syringes such asthose useful for delivery of drugs such as insulin. Typical suitablesyringes include systems comprising a prefilled vial attached to apen-type syringe such as the NOVOLET Novo Pen available from NovoNordisk, as well as prefilled, pen-type syringes which allow easyself-injection by the user. Other syringe systems include a pen-typesyringe comprising a glass cartridge containing a diluent andlyophilized pegylated interferon alpha powder in a separate compartment.

[0019] The term “patients having melanoma” as used herein means anypatient having melanoma and includes treatment-naive patients as well astreatment-experienced patients as well as patients in the Stage IIB orStage III cutaneous melanoma. All patients having melanoma arepreferably treated by wide excision of the primary melanoma lesion priorto initiation of the improved therapy of the present invention.

[0020] The term “treatment-naive patients” as used herein means patientswith melanoma including newly-diagnosed melanoma patients who have neverbeen treated with any chemotherapeutic drugs, e.g. dacarbazine (“DTIC”)or immunotherapy, e.g., IL-2 as well as any interferon, including butnot limited to interferon alpha, or pegylated interferon alpha. Alltreatment-naive patients having melanoma are preferably treated by wideexcision of the primary melanoma lesion prior to initiation of theimproved therapy of the present invention.

[0021] The term “treatment-experienced patients” as used herein meansthose patients who have initiated some form of chemotherapeutic drug,e.g., DTIC or immunotherapy including, but not limited tointerferon-alpha, IL-2 and GMCSF. All treatment-experienced patientshaving melanoma are preferably treated by wide excision of the primarymelanoma lesion prior to initiation of the improved therapy of thepresent invention.

[0022] The term “primary cutaneous melanoma” as used herein meanshistologically proven primary cutaneous melanoma as defined by thecurrent (1992) American Joint Committee on Cancer Staging Criteria(“AJCC”): in the AJCC Manual for Strategy of Cancer (4th edition)Philadelphia Pa. Lippincott Publishers 1992 and includes (a) nodenegative stage IIB disease with deep primary melanomas of Breslow depthmore than 4 mm and (b)node positive stage III disease defined, asfollows: (1) deep primary melanomas of Breslow depth more than 4 mm(designated CS1 PS1: T4N0M0); (2) primary melanomas of any tumor stagein the presence of N1 regional lymph node metastasis detected atelective lymph node dissection with clinically inapparent regional lymphnode metastasis (designated CS1 PS2: any TpN1M0); (3) clinicallyapparent N1 regional lymph node involvement synchronous with primarymelanoma of T1-4 (designated CS2 PS2: any TcN1M0); and (4) regionallymph node recurrence at any interval after appropriate surgery forprimary melanoma of any depth (designated CS2R: TxrN1M0 recurrent).Patients in groups 1 to 3 were required to enter this study within 56days of first primary melanoma biopsy. Patients with regional nodalrelapse in group 4 were required to enter this study within 42 days oflymphadenectomy.

[0023] All patients with stage III melanoma should be treated by wideexcision of the primary melanoma lesion.

[0024] Patients with clinically positive nodes in the groin, axilla orneck should have a full lymphadenectomy to surgically remove thesecites.

[0025] All surgery should be completed within 56 days prior torandomization into this clinical study.

[0026] The term “progression-free survival time” (“PFST”) as used hereinmeans the time from initiation of melanoma treatment in accordance withthe present invention to the documentation of disease progression orrecurrence by histological or cytological evidence.

[0027] The progression-free survival time expected for melanoma patientstreated in accordance with the method of this invention is at leastabout 4 years from initiation of the melanoma therapy of this invention;preferably the PFST is in the range of about 30 to about 43 months frominitiation of the melanoma therapy of this invention.

[0028] The increase in the progression-free survival time expected formelanoma patients treated in accordance with the method of thisinvention is greater than about 1.0 years to about 1.5 years compared tocontrol (observation).

[0029] The following criteria of treatment failure constitute the onlyacceptable evidence of disease recurrence or progression:

[0030] Lung/Liver:

[0031] Positive cytology or biopsy in the presence of a single newlesion or the appearance of multiple lesions consistent with metastaticdisease.

[0032] Central Nervous System:

[0033] A positive brain CT or MRI scan or Cerebrospinal fluid (CSF)cytology.

[0034] Cutaneous, Subcutaneous and Lymph Node Recurrence:

[0035] Positive cytology or biopsy.

[0036] Bone and Other Organs:

[0037] Positive cytology or biopsy in the presence of a single newlesion or the appearance of multiple lesions consistent with metastaticdisease identified by two different radiologic studies: i.e., positivegallium scan and contrast GI series or ultrasound, x-ray or CT ofabdomen for abdominal disease.

[0038] The term “prohibited medications” as used herein includes thefollowing:

[0039] a) Other chemotherapy, hormonal, immunologic, biologic orradiation therapy.

[0040] b) Colony stimulating factors including erythropoietin and G-CSF.

[0041] c) Other investigational drugs.

[0042] d) Chronic systemic corticosteroid therapy.

[0043] Melanoma patients treated in accordance with the method of thepresent invention should not receive any of the above-listed prohibitedmedications during the treatment period.

[0044] Pegylated interferon-alpha formulations are not effective whenadministered orally, so the preferred method of administering thepegylated interferon-alpha is parenterally, preferably by subcutaneous,IV, or IM, injection. Of course, other types of administration of bothmedicaments, as they become available are contemplated, such as by nasalspray, transdermally, by suppository, by sustained release dosage form,and by pulmonary inhalation. Any form of administration will work solong as the proper dosages are delivered without destroying the activeingredient.

[0045] The following Clinical Study Design may be used to treat melanomapatients in accordance with the method of the present invention. Manymodifications of this Clinical Study Design protocol will be obvious tothe skilled clinician, and the following Study Design should not beinterpreted as limiting the scope of the method of this invention whichis defined by the claims listed hereinafter.

Clinical Study Design

[0046] This is a Phase II/III randomized, controlled, multicenter,open-label study designed to assess he safety, efficacy, and impact onquality of life of PEG Intron (pegylated interferon alpha 2b i.e.PEG₁₂₀₀₀-interferon alpha 2b and INTRON® A (interferon alpha 2b), whichare each available from Schering Corporation, Kenilworth, N.J., and thepopulation pharmacokinetics of PEG Intron when given as adjuvant therapyin subjects with resected Stage III node-positive cutaneous melanoma. Itis anticipated that approximately 450 subjects will be enrolled, with225 subjects randomized to each treatment group.

[0047] Subjects will enter the study within 56 days of definitivesurgery for their Stage III melanoma and will be randomized to one ofthe two treatment groups shown below. Definitive surgery includes widesurgical excision of the primary melanoma and lymphadenectomy of allclinically positive nodes in the groin, axilla and neck. All surgeryshould be complete at least 56 days prior to randomization.

[0048] Group A: INTRON® A

[0049] 20 MlU/m²/day IV 5 days/week×4 weeks, followed by 10 MIU/m² SCTIW×48 weeks.

[0050] Induction Therapy:

[0051] 20 MIU/m²/day IV 5 days a week for 4 weeks

[0052] All subjects randomized to Treatment Group A, will begininduction therapy with intravenous INTRON® A, 20 million internationalunits/m²/day, 5 days/week for 4 weeks. Acetaminophen (500-1000 mg) maybe given in the clinic 30 minutes prior to receiving the first dose ofINTRON® A. Subjects should be observed for 2 hours after the first dose.Acetaminophen (500-650 mg PO q 4-6 hours) should be continued as needed,and should not exceed 3000 mg/day.

[0053] Maintenance Therapy:

[0054] 10 MIU/m² SC TIW for 48 weeks.

[0055] After induction therapy, subjects will continue on maintenancetherapy and receive INTRON® A, 10 million international units/m²/day, SCthree times weekly for 48 weeks.

[0056] Group B: PEG Intron:

[0057] PEG₁₂₀₀₀-interferon alpha-2b, 6.0 pg/kg, SC once weekly for 2years.

[0058] Subjects randomized to treatment Group B will receivePEG₁₂₀₀₀-interferon alpha-2b, 6.0 μg/kg, SC once weekly for 2 years.Acetaminophen (500-1000 mg) may be given in the clinic 30 minutes priorto receiving the first dose of PEG Intron. Subjects should be observedfor 2 hours after the first dose. Acetaminophen (500-650 mg PO q 4-6hours) should be continued as needed, and should not exceed 3000 mg/day.

Duration of Study and Visit Schedule

[0059] Treatment with either PEG₁₂₀₀₀-interferon alpha 2b (about 104weeks) or INTRON® A (52 weeks) will continue as scheduled unless thereis evidenced of disease recurrence, unacceptable toxicity, or thesubject requests that therapy be discontinued. Tolerability of therespective study treatment and quality of life will be assessed fromclinical observation, routine lab oratory testing, and quality of lifeassessments over the course of therapy. Following completion of therapy,subjects will continue to be followed for evidenced of diseaserecurrence and will complete quality of life assessments. If themelanoma recurs, further treatment will be at the discretion of thephysician. All subjects will be followed for survival, regardless ofwhen they discontinue therapy. Analyses of relapse-free and overallsurvival, regardless of when they discontinue therapy. Analyses ofrelapse-free and overall survival will be event driven.

[0060] The duration of this study is based upon achieving a therapeuticresponse, and will be determined for each subject individually.

[0061] The study population will include male and female patients withcutaneous melanoma and will be included if they meet the followinginclusion and exclusion criteria:

Subject Inclusion Criteria

[0062] A subject is eligible to participate in this study if he or she:

[0063] a) Subjects must have histologically documented primary cutaneousmelanoma meeting one of the following staging criteria:

[0064] Primary melanoma of any stage in the presence of NI regionallymph node metastases detected at elective lymph node dissection orsentinel node biopsy, with clinically inapparent regional lymph nodemetastasis (any PTN₁M₀).

[0065] Clinically apparent N1 or N2a regional lymph node involvementsynchronous with primary melanoma of T₁₋₄ (any pTrN_(1-2a)M₀).

[0066] Regional lymph node recurrence at any interval after appropriatesurgery for primary melanoma of any depth (any pTrN_(1-2a)M₀)

[0067] b) Subjects must have had all known disease completely resectedwith adequate surgical margins within 56 days prior to randomizationinto the study.

[0068] c) Subjects must have an ECOG performance status of 0 or 1 asdefined by Minna, J D, et al. “Cancer of the Lung” in DeVita V, et al.eds., Cancer: Principles and Practiced of Oncology, Lippincott,Philadelphia, Pa. 1989 at page 536.

[0069] d) Subjects must be between 18-70 years old.

[0070] e) Subjects must have adequate hepatic, renal and bone marrowfunction as defined by the following parameters obtained within 14 daysprior to initiation of study treatment.

[0071] 1) Hematology:

[0072] White Blood count (WBC) ≧3,000 cells/μL.

[0073] Hemoglobin concentration ≧9 g/dL.

[0074] 2) Renal and hepatic function:

[0075] Serum creatinine ≦2.0 mg/dL or calculated creatinine clearance of≧50 mL/minute.

[0076] Serum bilirubin <2 times the upper limit of normal (ULN), unlessdue to infiltration by disease.

[0077] AST/ALT (SGOT/SGPT) <2 times ULN.

[0078] f) has submitted a written voluntary informed consent beforestudy entry, is willing to participate in this study and will completeall follow up assessments.

Subject Exclusion Criteria

[0079] A subject is not eligible to participate in this study if he orshe:

[0080] a) Subjects who have received any prior chemotherapy,immunotherapy hormonal or radiation therapy for melanoma.

[0081] b) Subjects who have evidence of distant or non-regional lymphnode metastases, in-transit metastases, or positive lymph nodes with anunknown primary.

[0082] c) Subjects whose disease cannot be completely surgicallyresected because of gross extracapsular extension.

[0083] d) Subjects who have previously received interferon-α for anyreason. (Such patients however, are still considered treatable inaccordance with the method of this invention but are only excluded fromthis registration study.)

[0084] e) Subjects who have severe cardiovascular disease, i.e.,arrhythmias requiring chronic treatment, congestive heart failure (NYHAClass III or IV) or symptomatic ischemic heart disease as defined byBruce RA: Evaluation of Functional Capacity and Exercise Tolerance ofCardiac Subjects” in Mod. Concepts Cardiovasc Dis 1956; 25-321.

[0085] f) Subjects who have a history of neuropsychiatric disorderrequiring hospitalization.

[0086] g) Subjects with thyroid dysfunction not responsive to therapy.

[0087] h) Subjects with uncontrolled diabetes mellitus.

[0088] l) Subjects with a history of prior malignancy within the past 5years other than surgically cured non-melanoma skin cancer or cervicalcarcinoma in situ.

[0089] j) Subjects who have a history of seropositivity for HIV.

[0090] k) Subjects who are pregnant, lactating, or of reproductivepotential and not practicing an effective means of contraception.

[0091] l) Subjects with active and/or uncontrolled infection, includingactive hepatitis.

[0092] m) Subjects with a medical condition requiring chronic systemiccorticosteroids.

[0093] n) Subjects who are known to be actively abusing alcohol ordrugs.

[0094] o) Subjects who have received any experimental therapy within 30days prior to randomization in this study.

[0095] p) Subjects who have not recovered from the effects of recentsurgery.

Subject Discontinuation Criteria

[0096] It is the right and duty of the clinical investigator tointerrupt the treatment of any subject whose health or well being may bethreatened by continuation in this study.

[0097] Subjects may be discontinued prior to completion of this studyfor any of the following reasons:

[0098] a) Develops documented progression or recurrence of disease, asdefined herein above.

[0099] b) Has a clinically significant adverse event as determined bythe Principal Investigator.

[0100] c) Requests to be withdrawn from the study.

[0101] d) Is unable to complete the study evaluations/visits because ofunforeseen circumstances.

[0102] e) Develops other conditions for which, in the investigator'sopinion warrants withdrawal from the study

[0103] f) Develops severe depression or any other psychiatric disorderrequiring hospitalization.

[0104] g) Experiences a serious allergic response to the study drugmanifested by angioedema, bronchoconstriction or anaphylaxis.

[0105] h) Receives treatment with a prohibited medication as indicatedherein above.

[0106] l) Experiences recurrent toxicities despite dose modifications asdescribed herein below.

[0107] All subjects will be followed for survival, regardless of whenthey go off study. Subjects who discontinue for reasons other thanrecurrence of disease should also be followed for recurrence andsurvival.

Analysis of Primary and Secondary Endpoints

[0108] The primary endpoint will be progression-free survival (PFS)time, defined to be the time from randomization to progression or death.PFS will be assessed by clinical observation, with recurrence documentedby appropriate radiographic and histologic methods, and confirmed byIndependent Central Review.

[0109] The secondary endpoints will be overall survival, safety, qualityof life, and population pharmacokinetics (PK). Safety and tolerabilitywill be assessed from clinical observation and routine laboratorytesting over the course of therapy. Health-Related Quality of Life (HQL)will be assessed from an HQL questionnaire.

[0110] Population pharmacokinetics will be assessed from periodic serumsampling in the PEG Intron group.

[0111] Subjects enrolled in Group A who are not able to tolerate the IVinduction dose regimen despite dose modification, should stop the IVregimen but should not be discontinued from the study. After resolutionof toxicity, they may enter the INTRON® A maintenance phase with thefull maintenance dose.

What is claimed is:
 1. A method of treating a patient having melanoma which has been surgically removed, which comprises administering to such a patient a therapeutically effective dose of pegylated interferon alpha for a time period sufficient to increase progression-free survival time.
 2. The method of claim 1 wherein the pegylated interferon is pegylated interferon alpha-2a or pegylated interferon alpha-2b.
 3. The method of claim 2 wherein the patient is a treatment-naive patient.
 4. The method of claim 3 wherein the treatment-naive patient is one having newly diagnosed melanoma.
 5. The method of claim 1 wherein the patient is treatment-experienced patient.
 6. The method of claim 5 wherein the treatment experienced patient is intolerant to interferon alpha or resistant to interferon alpha.
 7. The method of claim 1 wherein the time period is at least about 24 months.
 8. The method of claim 1 wherein the pegylated interferon alpha administered after surgical excision of the primary melanoma.
 9. The method of claim 1 wherein the pegylated interferon alpha is pegylated interferon alpha-2b and the effective amount is in the range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered once a week.
 10. The method of claim 1 wherein the pegylated interferon alpha is pegylated alpha-2a and the effective amount is in the range of about 200 microgram to 250 administered once a week.
 11. A method of treating a patient having cutaneous melanoma which has been surgically removed which comprises administering to said patient an effective amount of pegylated interferon-alpha once a week for a time period sufficient to increase progression-free survival time.
 12. The method of claim 11 wherein the pegylated interferon alpha is pegylated interferon alpha-2b and the effective amount is in the range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered once a week.
 13. The method of claim 11 wherein the pegylated interferon alpha is pegylated alpha-2a and the effective amount is in the range of about 200 microgram to 250 administered once a week.
 14. The method of claim 11 wherein the time period is at least about 100 weeks.
 15. A method of treating a patient having cutaneous melanoma which comprises administering to such a patient about 3.0 micrograms/kg to about 9.0 micrograms/kg of pegylated interferon alpha-2b once a week for a time period sufficient to increase the progression-free survival time.
 16. The method of claim 15 wherein the time period is about 100 weeks.
 17. The method of claim 15 wherein about 4.5 to about 6.5 micrograms/kg of pegylated interferon alpha-2b is administered once a week.
 18. A method comprising the step of marketing a therapeutically effective dose of pegylated interferon alpha for administration to a patient with melanoma within about 60 days of surgery in a protocol extending for a time period of at least about 100 weeks.
 19. The method of claim 18 wherein the pegylated interferon alpha is pegylated interferon alpha-2b and the effective amount is in the range of about 3.0 micrograms/kg to 9.0 micrograms/kg administered once a week.
 20. The method of claim 18 wherein the pegylated interferon alpha is pegylated alpha-2a and the effective amount is in the range of about 200 microgram to 250 administered once a week. 